The invention relates to the treatment of patients suffering from neurotrauma, and particularly to methods for improving recovery from neurotrauma using procysteine compounds such as N-acetyl cysteine (xe2x80x9cNACxe2x80x9d) and L-2-oxothiazolidine-4-carboxylate (xe2x80x9cOTCxe2x80x9d) or its variants.
Acute physical insult to the central nervous system (xe2x80x9cCNSxe2x80x9d) very often leads to paraplegia, quadriplegia, speech and motor defects and other physical and mental conditions which impose a large burden on the individual afflicted, family and friends as well as society at large. Damage due to the primary mechanism of injury is generally aggravated by secondary mechanisms of injury including oxidative stress and accompanying inflammation. Secondary mechanisms of injury frequently cause greater tissue damage than the initial insult and can cause damage not only at the site of original injury but at adjacent sites as well.
Acute physical insult to the CNS (xe2x80x9cinsultxe2x80x9d) includes a wide range of sudden physical perturbations, including neurotrauma and vascular events such as stroke and aneurysm. Insult is distinguished from other disruption of the CNS such as ALS and neurotoxic compound poisoning by the nature of the injury and physiological responses resulting from the rapid onset and physical interference with CNS function associated with insult.
One approach to treating patients following insult is to repair the damage, for example, by promoting axon regeneration or through introduction of embryonic stem cells that differentiate and possible re-establish some of the disrupted circuitry; these are technically challenging approaches and so far have only been attempted in experimental animals.
A second approach is to minimize secondary mechanisms of tissue damage following insult. Prevention of damage is a much more efficacious treatment of neurotrauma than to attempt to repair damage once it has occurred. To date no fully satisfactory means of diminishing secondary damage following neurotrauma is available.
Unfortunately, efforts to reduce secondary damage have been hampered by difficulties in delivering suitable medicaments to the CNS. The blood-brain barrier normally restricts the passage of many molecules, and may prevent or delay delivery beyond the time available for full efficacy. Insult causes further changes in permeability and transport, further complicating treatment efforts.
Previous work has focused on reducing secondary injury following insult through the administration of methylprednisolone. However, studies to date suggest that methylprednisolone provides for only modest functional improvement and may lead to significant adverse side-effects.
L-2-oxothiazolidine-4-carboxylate (xe2x80x9cOTCxe2x80x9d) and N-acetylcysteine (xe2x80x9cNACxe2x80x9d) prodrugs which are believed to be useful in increasing glutathione (GSH) levels in tissues. GSH is believed to play a role in protecting tissues from damage due to oxidative stress.
It has been shown that pre-treatment of cultured neurons in vitro with OTC permits increased survival when the pre-treated neurons are subsequently injured. Moreover, in some studies where subjects were treated with OTC prior to the administration of neurotoxic GSH-depleting compounds, pre-treatment with OTC was reported to reduce the severity of GSH depletion observed. However, these examples are limited to situations where OTC was administered under normal, non-injured conditions where the normal permeability of the blood-brain barrier and the neuronal cell membrane does not appear to have been significantly altered.
It has been suggested that OTC may act by direct interaction of cysteine (formed from OTC) with the GSH-depleting compound, thereby reducing the demand for endogenous GSH. Thus, this mechanism of GSH preservation may be specific to GSH-depleting compounds and may not function in cases of GSH depletion arising from acute physical insult to the CNS (Gerard-Monnier, et al., Clin. Physiol. Biochem., 10:36-42, 1993).
Studies to date have focused on the use of OTC administered either prior to or substantially simultaneous with the administration of neurotoxic compounds. However, actual incidents of insult, for example in vehicle accidents, work place injuries, stroke or aneurysm usually occur several minutes or hours prior to the administration of expert medical attention and medication. This is particularly problematic as prior reports have tended to show either no increase in GSH concentrations immediately following OTC administration (a critical period for the control of secondary injury), or a decrease in GSH-concentrations during this period. Thus, the prior art suggests that OTC is poorly suited to use to improve functional recovery following insult.
Acute physical insult to the CNS causes disruptions in normal blood flow which may affect drug delivery and vascular permeability. In particular, blood flow may be disrupted at the site of injury and adjacent sites. This may interfere with the delivery of blood-born medicaments such as OTC.
Oxidative stress, including that resulting from insult, causes numerous cellular changes in affected neurons and glial cells as well as the endothelium of the blood vessels supplying the site of insult and adjacent sites. Among these are alterations in normal cell surface receptors and transport mechanisms. Thus, cells of the CNS experiencing oxidative stress do not necessarily take up some compounds which they would take up under normal conditions. In light of the changes to vascular and cellular permeability upon insult and resultant oxidative stress, it is unclear, in light of the prior art, if OTC could pass through the blood-brain barrier and be taken up by neurons in sufficient amounts following insult. Furthermore, it is not clear that the uptake of OTC, if it occurred, would result in descreased inflammation or improved functional recovery.
Thus, it is an object of the present invention to provide a method of improving functional recovery from insult.
In one embodiment of the invention there is provided a method of promoting functional recovery from an acute physical insult to the central nervous system, comprising administering to a mammalian patient which has suffered an acute physical insult to the central nervous system an initial dose of OTC, NAC or variants thereof.
In another embodiment of the present invention there is provided a method of promoting functional recovery from an acute physical insult to the central nervous system, comprising administering to a mammalian patient which has suffered an acute physical insult to the central nervous system an initial dose of OTC, NAC or a variants thereof following the insult and administering a number of subsequent doses of OTC or a variant thereof at subsequent time periods.
In another embodiment of the present invention there is provided a method of reducing oxidative stress in the central nervous system of a mammalian patient which has suffered an acute physical insult to the central nervous system, comprising administering an initial dose of OTC or a variant thereof to the patient following the insult.
In another embodiment of the present invention there is provided a method of reducing inflammation in the central nervous system of a mammalian patient which has suffered an acute physical insult to the central nervous system, comprising administering an initial dose of OTC or a variant thereof to the patient following the insult.
In another embodiment of the present invention there is provided a use of OTC or a variant thereof in the preparation of a medicament useful in promoting functional recovery of a mammalian patient which has suffered an acute physical insult to the central nervous system.
In another embodiment of the present invention there is provided a use of OTC or a variant thereof in the preparation of a medicament useful in reducing inflammation in the central nervous system of a mammalian patient which has suffered an acute physical insult to the central nervous system. Use of a combination of methylprednisolone and OTC or a variant thereof in the preparation of a medicament useful in promoting functional recovery of a mammalian patient which has suffered an acute physical insult to the central nervous system.
In another embodiment of the present invention there is provided a use of a combination of methylprednisolone and OTC or a variant thereof in the preparation of a medicament useful in reducing inflammation in the central nervous system of a mammalian patient which has suffered an acute physical insult to the central nervous system.
In another embodiment of the present invention there is provided a use of a combination of methylprednisolone and OTC or a variant thereof in the preparation of a medicament useful in reducing oxidative stress in the central nervous system of a mammalian patient which has suffered an acute physical insult of the central nervous system.